tbuckley/cabot-search huggingface dataset:
IMMU-55. THERAPEUTIC WINDOW ENABLING ERADICATION OF RESIDUAL GLIOMA STEM CELLS BY INTRACRANIAL NK CELL AND EXTRACELLULAR VESICLE-MEDIATED THERAPY FOLLOWING TEMOZOLOMIDE-INDUCED TUMOUR DEPOPULATION
Authors: Brian Meehan, Lata Adnani, Xianbing Zhu, Nadim Tawil, Delphine Garnier, Ichiro Nakano, Sidong Huang, Janusz Rak
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is an incurable brain cancer, where dismal outcomes result from disease recurrence driven by tumour-initiating glioma stem cells (GSCs). GSCs survive and expand in the brain after surgery, radiation and temozolomide (TMZ) amidst weak immune and natural killer (NK) cell surveillance. NK cell-mediated killing of GBM cells occurs at effector to target rations precluding effective eradication as enforced by clinical trials with autologous NK cells in an adjuvant setting. Here we explore in a human GSC xenograft model whether tumor depopulation using high dose Temozolomide (TMZ) could create a window of curative opportunity for endogenous or exogenous NK cells. We observed that while subcutaneous (sc) xenografts of patient derived GSCs are infiltrated by endogenous functional (NCR1+) NK cells in SCID mice, the corresponding intracranial (ic) tumours remained NK cell depleted. In NK-deficient NSG mice, neither site contained functional NK cells. Notably, while TMZ caused near complete regression of GSC xenografts in both strains of mice and both locations (sc and ic), this was followed by recurrence of drug resistant lesions in all cases except NK-infiltrated sc SCID xenografts. This effect was obliterated by anti-sialo GM1 treatment. To explore whether direct delivery of NK cells into depopulated intracranial tumours would change the lethal course of the disease, mice were injected with GSCs ic, and upon tumour formation were treated with a sequence of TMZ (systemically), and two days later with irradiated NK92MI. Remarkably, this combined therapy completely obliterated recurrent disease. To assess whether NK92MI cells could be replaced by their derived extracellular vesicles (NK-EVs), the latter were injected i.c. post TMZ in GSC xenograft bearing mice. A single injection of NK-EVs resulted in tumour eradication in some but not all mice. Thus, chemotherapy-dependent tumour depopulation may create a unique window of opportunity for curative NK-mediated immunotherapy in GBM.
CSIG-03. SHH PATHWAY ACTIVATION IN DEDIFFERENTIATION DURING TUMOUR PROGRESSION IN MPNST
Authors: Rebeca Yakubov, Severa Bunda, Gelareh Zadeh
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Malignant peripheral nerve sheath tumours (MPNST) are highly aggressive sarcomas with little progress on outcomes and treatment strategies. Previous work conducted in our lab used unsupervised analyses of methylome and transcriptome profiles of 108 peripheral nerve sheath tumours to uncover two subgroups of MPNSTs that predict progression-free survival, MPNST-G1 (characterized by SHH pathway activation) and MPNST-G2 (characterized by WNT/ß-catenin/CCND1 pathway activation). Further, single nuclear RNA-sequencing revealed that MPNST-G1 and MPNST-G2 cells resemble neural crest-like and Schwann cell precursor-like cells, respectively. PURPOSE &amp; HYPOTHESIS To examine the expression of transcription factors (TWIST1, SOX9, SNAI2, OTX2, PAX3, and PAX6) known to play canonical roles in the early neural crest cell specification in MPNST-G1 cells. We speculate that MPNST-G1 cells will display overexpression of these transcription factors compared to MPNST-G2 cells and that Sonidegib (SMO inhibitor) will revert dedifferentiation by decreasing activation of the SHH pathway. METHODS Dedifferentiation transcription factor expression and the effects of SMO activation and inhibition in MPNST-G1 and MPNST-G2 cells were analyzed using RT-PCR and western blotting. Alamar blue and Trypan blue assays were used to determine the effect of SMO inhibition on proliferation. RESULTS Compared to MPNST-G2 cells, MPNST-G1 cells displayed elevated expression of dedifferentiation transcription factors, SMO inhibition was able to reverse these effects. Conversely SMO activation induced the expression of these factors and induced an increase in proliferation. CONCLUSIONS The SHH pathway activation promotes the expression of important transcription factors in dedifferentiation. This finding provides insights into the transformation process of MPNST and novel therapeutic options for these lethal cancers.
RBIO-01. GAMMATILE ® (GT) AS A BRACHYTHERAPY PLATFORM FOR RAPIDLY GROWING BRAIN METASTASIS
Authors: Rajiv Dharnipragada, Clara Ferreira, Margaret Reynolds, Rena Shaw, Kathryn Dusenbery, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND A subset of brain metastasis (BM) shows rapid recurrence post-initial resection or aggressive tumor growth between interval scans. Here we provide a pilot experience in the treatment of these brain metastasis with GammaTile ® (GT), a collagen tile-embedded Cesium 131 (131Cs) brachytherapy platform. METHODS We identified ten consecutive patients (2019-2023) with brain metastasis that showed either 1) symptomatic recurrence while awaiting post-resection radiosurgery or 2) enlarged by &amp;gt;25% of tumor volume on serial imaging and underwent surgical resection followed by GT placement. Procedural complication, 30-day readmission, local control, and overall survival were assessed. RESULTS For this cohort of ten BM patients, three patients suffered tumor progression while awaiting radiosurgery and seven showed &amp;gt;25% tumor growth prior to surgery and GT placement. There were no procedural complications or 30-day mortality. All patients were discharged home, with a median hospital stay of two days (range: 1-9 days). 4/10 patients experienced symptomatic improvement while the remaining patients showed stable neurologic conditions. With a median follow-up of 186 days (6.2 mo, range: 69-452 days), no local recurrence was detected. The median overall survival (mOS) for the newly diagnosed BM was 265 days from the time of GT placement. No patients suffered from adverse radiation effects. CONCLUSION Our pilot experience suggests that GT offers favorable local control and safety profile in patients suffering from brain metastases that exhibit aggressive growth patterns and support the future investigation of this treatment paradigm.
SURG-46. PRIMARY MALIGNANT MELANOMA, AN ATYPICAL PRESENTATION IN THE CERVICAL SPINE
Authors: Larrey Kamabu, Louange Maha Kataka, Moses Galukande, Hervé Monka Lekuya
Journal: Neuro-Oncology (2023)

Abstract Few studies have documented the occurrences of melanomas in the cervical spine. one percent of all malignant melanoma cases are primary melanoma of the central nervous system, which is extremely uncommon and nonspecific. We aimed to report a case of uncommon presentation of primary melanoma in the cervical spine. This a 59-year-old, male who presented with a 2-year history of anterior neck swelling, severe pain and tingling sensation in the left shoulder and arm which worsened in the previous 6 months. He developed weakness and paresthesia in the left upper arm and progressive gait disturbance of the left lower limb. Physical examination revealed masses in the left cervical and right submandibular region. There was left upper and lower extremities hemiparesis and hemi hypoesthesia. MRI showed hyperintense lesion on T1WI and hypointense on T2WI originating from the cervical spine and involving the vertebral bodies and paravertebral soft tissues. The patient underwent surgery, a black tumor was extracted, and histology revealed malignant melanoma. This case is presented in order to highlight the significance of and challenges associated with making a preoperative diagnosis of primary cervical melanoma with atypical radiological characteristics. Patients with extradural lesions that show hyperintensity on T1 weighted images and hypo intensity on T2-weighted images should have spinal melanoma examined as a possible differential diagnosis.
MODL-30. UTILIZING SERUM-FREE CO-CULTURE MODELS FOR IN-VITRO MODELING OF TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA
Authors: Hasan Alrefai, Manoj Kumar, Lauren Nassour, Taylor Schanel, Andee Beierle, Joshua Anderson, Patricia Hicks, Christopher Willey
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The GBM tumor microenvironment consists of various cancerous and non-cancerous cells that influence GBM growth, invasion, angiogenesis, and resistance to chemoradiation. In-vitro models of GBM often lack multiple cell types. Some addressed this by using multicellular models with macrophages and astrocytes; however, these models employ serum-containing media, which causes GBM brain-tumor initiating cells to lose their stem-like properties. Moreover, these models use IL-4/13 polarized macrophages (M2), despite tumor-associated macrophages (TAMs) not adhering to the M2 phenotype. Thus, there is a need to develop physiologically accurate in-vitro models of GBM. METHODS We transitioned THP-1 monocytes from serum-containing RPMI 1640 to serum-free TheraPEAKTM X-VIVOTM-15 media. Monocytes were stimulated towards a macrophage-like state with PMA and polarized by co-culturing with GBM patient-derived xenograft (PDX) lines using transwell inserts. Macrophage polarization was characterized through cytokine arrays, invasion, angiogenesis, and phagocytosis assays, comparing them to resting (M0), pro-inflammatory (M1), and M2 macrophages. RESULTS THP-1 monocytes grown in X VIVO-15 media exhibited similar proliferation rates to those in RPMI 1640 for up to 48 hours. However, at 72 hours, there was a slight decrease in proliferation rates in X VIVO-15 media (p&amp;lt; 0.0001). Macrophages polarized by the GBM PDX line, JX39P-RT, did not exhibit the cytokine expression profile of any other group. M2 macrophages displayed higher phagocytic capacity (25%) of JX39P-RT compared to M0, M1, and TAMs (&amp;lt; 15%, p&amp;lt; 0.01). M1 macrophages showed significantly higher invasion rates than M0, M2, and JX39P-polarized TAMs. CONCLUSIONS We have demonstrated a serum-free method by which we can polarize macrophages towards a GBM-supportive phenotype that differs molecularly and functionally from M0, M1, and M2 macrophages. This high-fidelity method of modeling TAMs in GBM will aid in the development and testing of innate immunomodulatory therapeutics that may one day enter the clinic in hopes of improving GBM outcomes
CTNI-62. INTERIM DATA ON DUAL INHIBITION OF POST-RADIOGENIC ANGIO-VASCULOGENESIS BY OLAPTESED PEGOL (NOX-A12) AND BEVACIZUMAB IN GLIOBLASTOMA FROM THE FIRST EXPANSION ARM OF THE PHASE 1/2 GLORIA TRIAL
Authors: Frank Giordano, Julian Layer, Sonia Leonardelli, Lea Friker, Christina Schaub, Thomas Zeyen, Elena Sperk, Peter Hambsch, Christoph Oster, Franziska Grau, Daniel Paech, Wolf Müller, Torsten Pietsch, L Christopher Schmeel, Oliver Grauer, Mirjam Renovanz, Ghazaleh Tabatabai, Sied Kebir, Sotirios Bisdas, Erdem Güresir, Martin Glas, Clemens Seidel, Michael Hölzel, Ulrich Herrlinger
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND We recently reported favorable safety and preliminary efficacy signals for treatment with radiotherapy (RT), the CXCL12 neutralizing L-RNA aptamer olaptesed pegol (NOX-A12) and bevacizumab for glioblastoma (GBM) in the German multicenter phase 1/2 GLORIA trial (NCT04121455). Here, we report updated outcomes on dual inhibition of vasculogenesis (NOX-A12) and angiogenesis (bevacizumab). METHODS Six patients with incompletely resected, MGMT-unmethylated GBM, ECOG≤ 2 were enrolled, receiving standard RT (60 Gy in 30 fractions), continuous i.v. infusions of NOX-A12 (600 mg/week) and i.v. infusions of bevacizumab (10 mg/kg q2w). The primary endpoint was safety. Secondary endpoints included radiographic response according to modified RANO criteria (mRANO) as well as perfusion/diffusion imaging. RESULTS Combination treatment was well-tolerated and safe. Of all G≥2 AEs (n = 79), two G2 events (2.5%) were deemed related to NOX-A12 only. There were no dose-limiting toxicities and no treatment-related deaths. At a median follow-up of 14.6 months, one patient deceased due to distant leptomeningeal spread. Median overall survival (OS) has not yet been reached. With an overall response rate (ORR) of 83.3% under treatment, one patient achieved confirmed complete response (CR), four patients partial response (PR) and one patient stable disease (SD). The median best response under treatment was -68.9% (-53,8% to -100%) for target lesion sums and -100% (-99.9% to -100%) for non-target lesion (NTL) sums. In all three patients with NTLs at least one lesion disappeared. The median best change from baseline of the highly perfused-tumor fraction was -98.2% (-61.3% to -100%) and the median best change of the apparent diffusion coefficient was 24.9% (7.3% to 59.1%). CONCLUSIONS Interim data of the ongoing trial confirm the previously established safety profile of NOX-A12 for combinatory treatment with bevacizumab while demonstrating improved efficacy with deeper and longer-lasting responses and a higher ORR compared to treatment with RT and NOX-A12 only.
CTNI-47. DOSE ESCALATION OF ASTX727 IN ADULT PATIENTS WITH RECURRENT/PROGRESSIVE NON-ENHANCING IDH MUTANT GLIOMAS
Authors: Isabel Arrillaga-Romany, Julie Miller, Jorg Dietrich, Scott R Plotkin, Elizabeth Gerstner, Justin T Jordan, Deborah Forst, Eudocia Lee, Patrick Wen, David Reardon, Lakshmi Nayak, Tracy Batchelor, Ugonma Chukwueke, Miguel Rivera, Nathalie Agar, Daniel Cahill, Bradley Bernstein
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND IDH mutant gliomas typically display a hypermethylation pattern known as the glioma CpG island methylator phenotype (G-CIMP) which results in gene activation that promotes gliomagenesis. This study aims to reverse this methylation signature and disrupt tumor growth via treatment with an oral demethylating agent. METHODS This is 2-stage clinical trial investigating oral ASTX727 (decitabine + cedazuridine, a cytidine deaminase inhibitor, as a combination tablet) in patients with recurrent primarily non-enhancing IDH mutant gliomas. The Dose Escalation Stage consisted of a single arm 3 + 3 design. The primary objective was to establish the MTD and assess safety in this patient population. RESULTS Eleven pts (F = 45%, M = 55%) with a median age of 44 yrs (range 26-61 yrs) were enrolled. Two DLTs (grade 4 neutropenia for &amp;gt;72 hrs) were observed in 5 pts enrolled at the starting dose (35 mg decitabine/ 100 mg cedazuridine for 5 consecutive days). Six additional patients were enrolled at dose level -1 (35 mg decitabine/100 mg cedazuridine for 4 consecutive days). There were no DLTs at dose level -1 and this was declared the MTD. Grade ≥ 3 AEs included neutropenia (5 pts), leukopenia (1 pt), lymphopenia (1 pt), hyponatremia (1 pt) and increased ALT (1 pt). Best treatment response was SD in 11 patients. At the time of last follow-up (5/15/23) 10 pts have discontinued treatment (8 for PD, and 2 based on physician decision), 2 pts (18%) have died due to disease progression, 8 pts remain alive and in follow-up, and 1 patient remains on treatment. Median duration on treatment was 212 days (range 36 days – not reached). CONCLUSIONS ASTX727 was well tolerated in patients with recurrent non-enhancing IDH mutant glioma at dose level -1 with no DLTs . A surgical expansion cohort is currently enrolling to confirm drug target engagement and explore pharmacodynamics.
NIMG-69. LEPTOMENINGEAL METASTASES IN IDH-WILDTYPE GLIOBLASTOMAS REVISITED: COMPREHENSIVE ANALYSIS OF INCIDENCE, RISK FACTORS, AND PROGNOSIS BASED ON POSTCONTRAST FLAIR IMAGING
Authors: Yae Won Park, Sung Soo Ahn, Seok-Gu Kang, Jong Hee Chang, Se Hoon Kim
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND To comprehensively investigate the incidence, risk factors, and prognosis of leptomeningeal metastases (LM) in isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients. METHODS Total 913 IDH-wildtype glioblastoma patients with complete molecular information on IDH mutation and MGMT promoter methylation status were enrolled between 2004 and 2022. LM diagnosis was performed with MRI including postcontrast FLAIR and CSF cytology. Logistic regression analysis for LM development at initial diagnosis and recurrence was performed with clinical, surgical, imaging, and molecular data. The overall survival (OS) was compared between patients with and without LM. RESULTS The incidence of LM was 21.8% (199 patients) among patients with IDH-wildtype glioblastoma, with 11.5% (105 patients) at initial diagnosis, and 10.3% (94 patients) at recurrence. Male sex (odds ratio [OR]: 1.74, P = 0.017), MGMT promoter unmethylation (OR: 1.48, P = 0.048), nonlobar location (OR: 2.27, P &amp;lt; 0.001), and presence of necrosis (OR: 3.64, P &amp;lt; 0.001) were independent predictors of LM at initial diagnosis, whereas ventricular opening during surgery (OR: 2.96, P &amp;lt; 0.001) was the only independent predictor of LM at recurrence. The median OS was 16.2 months (interquartile range [IQR]: 9.6-30.4) in patients with LM and 19.3 months (IQR: 12.1-38.5) in patients without LM (log-rank test; P = 0.001). CONCLUSION The incidence of LM is high in patients with IDH-wildtype glioblastoma. Aggressive clinical, imaging, and molecular factors are correlated with LM at initial diagnosis, whereas ventricular entry warrant imaging surveillance for LM at recurrence. The prognosis of LM is not discouraging as expected, and promote reconsideration of focused clinical trials.
CSIG-01. DEFINING THE INVOLVEMENT OF THE PERIVASCULAR NICHE IN BRAIN TUMOR METASTASES
Authors: Vernon Fong, Namal Abeysundara, Bryn Livingston, Cory Richman, Anders Erickson, Michael Taylor
Journal: Neuro-Oncology (2023)

Abstract Medulloblastomas (MB) are the most prevalent malignant pediatric brain tumors, originating in either the cerebellum or the dorsal brainstem. They are classified into four distinct subgroups (WNT, SHH, Group 3, and Group 4), characterized by unique gene expression profiles, metastatic patterns, and recurrence rates. Metastatic progression of MB is frequently associated with poor prognosis, affecting approximately 30% of patients at diagnosis. Despite considerable research on primary tumors, there are currently no approved specific treatments for MB leptomeningeal metastases. Thus, gaining further insights into metastatic MB and developing targeted therapies are imperative. The leptomeningeal niche, where metastatic MB tumor cells reside, comprises a complex network of blood vessels supported by perivascular cells, including pericytes, smooth muscle cells, and fibroblasts. However, the specific adhesion molecules and signaling pathways within the leptomeningeal niche that contribute to tumor cell colonization remain elusive. In this study, we hypothesize that the perivascular niche plays a critical role in the colonization and survival of metastatic cells within the leptomeninges. To investigate this, we employed an innovative sLP-mCherry niche labeling system in conjunction with single-cell RNA sequencing to spatially identify and examine the perivascular cells neighboring metastatic MB tumor cells. Through our analysis, we identified upregulated genes associated with cholesterol export in tumor-associated perivascular cells, suggesting their potential involvement in supporting metastatic cell colonization. To further explore this mechanism, we utilized CRISPR and lentiviral overexpression constructs to modulate cholesterol uptake in MB cell lines, observing subsequent changes in metastatic burden. In summary, our study elucidates the importance of the perivascular niche in metastatic medulloblastomas and provides novel insights into the molecular mechanisms that drive tumor cell colonization within the leptomeninges. These investigations into the lipid transport mechanism in the vascular microenvironment opens doors for the development of innovative treatments targeting MB metastases.
CNSC-02. GLUTAMATERGIC SYNAPTIC INPUT DRIVES BRAIN METASTASIS OF BREAST CANCER AND MELANOMA
Authors: Matthia Karreman, Varun Venkataramani, Linh C Nguyen, Nils Hebach, Cedric Tehranian, Chanté Mayer, Lasse Meyer, Sadaf Mughal, Lukas Geckeler, Dana Westphal, Michael Breckwoldt, Wolfgang Wick, Thomas Kuner, Frank Winkler
Journal: Neuro-Oncology (2023)

Abstract The nervous system is implicated in pathology of both cranial and extracranial cancers. In glioblastoma, direct excitatory glutamatergic synapses between neurons and cancer cells were discovered. Importantly, these neuron-cancer contacts drive glioblastoma proliferation and invasion. However, such synapses have not yet been documented in other types of brain cancer. In the context of brain metastases, indirect, peri-synaptic contacts between breast cancer cells and neurons were observed, which promote brain metastatic growth through glutamatergic signaling via NMDA receptors on the neoplastic cells. Recently, two studies have demonstrated that neuronal activity supports the growth of both the primary tumor and brain metastases from neuroendocrine carcinoma small cell lung cancer. In the work presented here, we demonstrate direct neuron-cancer synapses in early-stage brain metastases originating from breast cancer and melanoma. These synapses exhibited the typical structural features observed in synaptic connections and induced postsynaptic currents in the cancer cells through the activation of AMPA subtype glutamate receptors. Importantly, genetic and pharmacological perturbation of these receptors reduces the number of brain metastases and the overall metastatic burden in preclinical models of breast cancer and melanoma. These results uncover a previously unknown form of direct communication between neurons and brain-metastatic breast cancer and melanoma tumor cells. This neuronal-tumor synaptic interaction demonstrates the significance of the neuronal microenvironment in the early stages of the brain metastatic cascade. Furthermore, it unveils a potential therapeutic vulnerability associated with the neuronal microenvironment, suggesting that targeting the synaptic communication between neurons and cancer cells could be a promising strategy to impede the progression of brain metastases.